Department of Plastic Surgery, University of Tokyo, Tokyo, Japan.
Stem Cells Transl Med. 2012 Aug;1(8):615-26. doi: 10.5966/sctm.2012-0032. Epub 2012 Jul 27.
Dermal papilla cells (DPCs) have the potential to induce differentiation of epithelial stem cells into hair, and Wnt signaling is deeply involved in the initiation process. The functional limitation of expanded adult DPCs has been a difficult challenge for cell-based hair regrowth therapy. We previously reported that 1α,25-dihydroxyvitamin D(3) (VD(3)) upregulates expression of transforming growth factor (TGF)-β2 and alkaline phosphatase (ALP) activity, both features of hair-inducing human DPCs (hDPCs). In this study, we further examined the effects and signaling pathways associated with VD(3) actions on DPCs. VD(3) suppressed hDPC proliferation in a dose-dependent, noncytotoxic manner. Among the Wnt-related genes investigated, Wnt10b expression was significantly upregulated by VD(3) in hDPCs. Wnt10b upregulation, as well as upregulation of ALPL (ALP, liver/bone/kidney) and TGF-β2, by VD(3) was specific in hDPCs and not detected in human dermal fibroblasts. Screening of paracrine or endocrine factors in the skin indicated that all-trans retinoic acid (atRA) upregulated Wnt10b gene expression, although synergistic upregulation (combined atRA and VD(3)) was not seen. RNA interference with vitamin D receptor (VDR) revealed that VD(3) upregulation of Wnt10b, ALPL, and TGF-β2 was mediated through the genomic VDR pathway. In a rat model of de novo hair regeneration by murine DPC transplantation, pretreatment with VD(3) significantly enhanced hair folliculogenesis. Specifically, a greater number of outgrowing hair shafts and higher maturation of regenerated follicles were observed. Together, these data suggest that VD(3) may promote functional differentiation of DPCs and be useful in preserving the hair follicle-inductive capacity of cultured DPCs for hair regeneration therapies.
真皮乳头细胞（DPC）具有诱导上皮干细胞分化为毛发的潜能，而 Wnt 信号通路在起始过程中起着重要作用。体外扩增的成人 DPC 功能有限，这是细胞再生治疗的一个难题。我们之前报道过 1α，25-二羟维生素 D（VD3）可上调转化生长因子（TGF）-β2 和碱性磷酸酶（ALP）的表达，这些都是诱导人真皮乳头细胞（hDPC）分化的特征。在本研究中，我们进一步研究了 VD3 对 DPC 的作用及其相关信号通路。VD3 以剂量依赖性、非细胞毒性的方式抑制 hDPC 的增殖。在所研究的 Wnt 相关基因中，Wnt10b 的表达在 hDPC 中被 VD3 显著上调。VD3 不仅可特异性上调 hDPC 中的 Wnt10b、ALPL（ALP，肝/骨/肾）和 TGF-β2，还能促进体外扩增的 hDPC 向毛囊细胞分化。在皮肤中筛选旁分泌或内分泌因子表明，全反式维甲酸（atRA）可上调 Wnt10b 基因的表达，但未见协同上调（atRA 和 VD3 联合作用）。维生素 D 受体（VDR）的 RNA 干扰表明，VD3 对 Wnt10b、ALPL 和 TGF-β2 的上调是通过基因组 VDR 途径介导的。在利用小鼠 DPC 移植诱导新生毛发生长的大鼠模型中，VD3 预处理可显著增强毛囊发生。具体表现为，更多的毛发向外生长，再生毛囊的成熟度更高。综上所述，这些数据表明 VD3 可能促进 DPC 的功能分化，有助于维持体外培养 DPC 诱导毛发生长的能力。
